The gender line

Say what you will about Mars and Venus, but anatomically, male and female hearts look the same. When healthy, both should be about the size of a fist. Both have three main coronary arteries, the large blood vessels that wrap around the outside of the heart, supplying blood, oxygen and nutrients to keep each one pumping properly.

But when heart disease sets in, researchers are learning, gender can dictate major differences in how it actually develops and the parts of the heart it affects. These differences have implications for how heart disease is diagnosed — and treated. They may also change how doctors predict who is at risk for the most catastrophic of cardiac events, sudden cardiac arrest (see related story).

As is true with most gender differences, however, the issue is not as clear cut as XX versus XY, and cardiologists warn that heart disease can't be divided into male and female forms.

Men and women can have coronary artery disease in which those main, large arteries are plugged up by fatty, athlerosclerotic plaques. These blockages greatly increase the risk of a heart attack, sudden cardiac arrest, stroke and heart failure. But far fewer women show up with this "classic" form of heart disease.

"When it comes to acute heart attacks and sudden death [from cardiac arrest], women have these kinds of events much more often without any obstructions in their coronary arteries," says Dr. Amir Lerman, a cardiologist at the Mayo Clinic in Rochester, Minn.

Instead, it appears that a significant portion of women suffer from another form of heart disease altogether, one that affects not the superhighway coronary arteries but rather the smaller arteries, called microvessels, that deliver blood directly to the heart muscle tissue. What researchers are learning about this new form of heart disease may explain why some patients experience different heart-related symptoms and why women, as a group, have higher mortality and poorer outcomes from the suite of disorders that make up cardiovascular disease.

Cardiovascular disease kills more Americans, men and women, of all ethnicities than any other cause. Each year since 1984, more women (432,709 in 2006) have died of cardiovascular disease -- which includes not just heart disease and heart attacks but also stroke and heart failure -- than men (398,563 in 2006). But more men experience and die of coronary heart disease and heart attacks than do women each year. Men develop heart disease on average 10 years earlier than women. But women who have a heart attack seem to fare worse right after the event and also suffer a poorer quality of life.

Figuring out what underlies these gender differences has become a priority among cardiology researchers. If they succeed, doctors could predict, diagnose and treat all varieties of heart disease more effectively.

"Men and women today smoke the same, are equally obese, have the same levels of physical activity and stress, and they eat pretty much the same," says Dr. C. Noel Bairey Merz, director of the Women's Heart Center at the Cedars-Sinai Heart Institute in Los Angeles. "It doesn't look like there are gender differences in the traditional risk factor pathways." (Translation: Prevention efforts are the same for men and women.)

But Bairey Merz and other researchers around the country have found that while men predominantly suffer from coronary artery disease, women predominantly suffer from what she proposes calling ischemic heart disease. In this form, also referred to as microvessel disease or microvascular dysfunction, the smaller arteries of the heart do not function properly.

Normally, these vessels regulate the supply of blood to the heart tissue when demands are higher — at times of stress, for example, or during exercise when the heart pumps faster. But in many women (and some men), this process becomes dysfunctional, and the microvessels fail to respond properly. This can lead to ischemia, a starving of the heart tissue of oxygen and nutrients. If severe enough or prolonged, this ischemia can cause the same end result that plugged-up arteries cause — not enough blood supply when demand is high, leading to a heart attack.

Bairey Merz believes this problem, which looks very different from coronary artery disease, probably underlies the generally worse cardiac outcomes for women because it is not being recognized and treated as heart disease.

To understand why that may be the case, it helps to compare the symptoms, diagnosis and treatment of these two types of heart disease.

Symptoms versus no symptoms

Only about half of patients will have what doctors call the " Hollywood heart attack," clutching their chest, sweating, face in agony as an elephantine crushing weight attacks them. The other half will experience what are called atypical symptoms, such as fatigue, pain in their arms, shoulders, back or jaw, and shortness of breath, or they'll have no symptoms at all. Women are much more likely to fall into this group, something physicians have long known.

When patients show up in the doctor's office distressed by symptoms of potential heart disease, a majority of men and a significant portion of women will show signs of coronary artery disease in diagnostic tests. Those tests may include an electrocardiogram (EKG) and an exercise stress test on a treadmill to detect abnormal heart rhythms, and possibly an angiogram, an invasive technique that shows in real time the blood flow through coronary arteries.

In a typical angiogram, a catheter, or small plastic tube, is threaded through the femoral artery in the patient's groin to just outside the heart. A dye is then injected that shows up on a special type of X-ray — a cardiologist can then see whether any blockages prevent the dye, or blood, from flowing freely.

But some women with coronary artery disease appear to form plaques that do not create blockages but rather build up uniformly along the inside of their large arteries, narrowing them. This is difficult to see in an angiogram.

Further, the exercise stress test and angiogram will not pick up problems occurring in the microvessels. This means a majority of women, even those complaining of chest pains or fatigue, (and some portion of men too) may be given an "all clear" diagnosis simply because their coronary arteries show no signs of blockage. In fact, treadmill tests are known to give a higher rate of false positives in women.

"On average, these women are probably told their symptoms are not coming from their heart," because their large arteries appear clear, says Bairey Merz.

That may mean lead to misdiagnosis and patients being sent home with no treatment, says Dr. Martha Gulati, associate director of the Center for Women's Cardiovascular Health at Northwestern Memorial Hospital in Chicago.

"We need to give a different message. I'd say to women and their doctors, ‘Don't stop there,' " she says, but instead look for signs of microvessel disease as well. Tests for microvessel disease do exist at some research hospitals, but they are not standard clinical practice.

At Mayo, Lerman does what he calls a "functional angiogram" — in addition to a traditional angiogram — to measure whether the microvessels are responding to stress appropriately in men and women. The test starts the same as the imaging angiogram, with a catheterization, but then the doctor gives a drug that raises the heartbeat to simulate stress. Next, a Doppler radar probe measures the change in the speed of the blood flowing to the heart.

Neither diagnostic test is considered standard protocol, and each is being evaluated for how effectively it detects microvessel disease.

Lerman says that among patients he's studied who have no signs of blocked large arteries but who have microvessel disease, 30% to 40% are men.

Some get no therapy

Currently, says Bairey Merz, too many patients who most likely have microvessel disease "are not put on the lifesaving therapies that help with ischemia," such as low-dose aspirin and other drugs known to help improve blood flow in the heart.

She and other cardiologists who study microvessel disease think that these patients should be offered the same drug treatments used for coronary artery blockages until more specific treatments are developed for this problem. The drugs used to treat blockages include statins to lower so-called bad, or LDL, cholesterol and prevent more plaque buildup and medicines such as aspirin, ACE inhibitors, beta blockers and nitroglycerin to improve blood flow around the blockages.

If blockages are severe, they may also be treated with interventions such as a balloon angioplasty to open up a blockage, a wire mesh stent to hold a blockage open or bypass surgery to create a new route for the blood to take.

Many questions remain about this different form of heart disease. Key among them: What causes the small vessels to react improperly? And what is the best way to treat it? Answering these questions will be expensive; not doing so will be even more expensive, Bairey Merz says. Not only would too many human lives be lost to missed heart disease, but the costs would add up in terms of repeat hospital and doctors visits and repeat angiograms of patients whose symptoms persist.

Bairey Merz and her collaborators are testing drugs that lower blood pressure and cause vessels to open up in women with microvessel disease. She and Lerman are also investigating Viagra-like drugs, which also cause vessels to dilate.

Why men appear to be more susceptible to coronary artery disease and why women appear to fall prey more often to microvessel disease also remains a mystery. Some researchers believe it could be related to hormonal differences or to the fact that women are more prone to chronic inflammation.

Regardless, some cardiologists are reluctant to classify women and men as suffering from different types of heart disease. "The danger of reclassifying the condition for women is that one would tend to forget or discount the fact that a great deal of [heart disease] in women is very similar if not identical to men," says Dr. Marian Limacher, a cardiologist at that University of Florida in Gainesville.

She's cautious because it's unclear whether microvessel problems are a spectrum of the same disease that leads to coronary artery blockages or represents another disorder altogether. Any physician evaluating a patient with cardiac symptoms should first rule out traditional coronary obstruction, which would benefit from proven treatments, she says.

Even symptoms do not fall along clear gender lines, she notes, with atypical symptoms increasing with age for men and women. "Symptoms span a spectrum for both men and women. The real message is that anytime your body is telling you something is wrong, pay attention to it."